PEOPLE’S DEMOCRATIC REPUBLIC OF ALGERIA
MINISTRY OF HIGHER EDUCATION
AND SCIENTIFIC RESEARCH
UNIVERCITY OF BROTHERS MENTOURI-CONSTANTINE
FACULTY OF EXACT SCIENCES
DEPARTMENT OF CHEMISTRY
Order N°………...
Series………
THESIS
SUBMITTED IN PARTIAL FULFILLMENT OF REQUIREMENT
FOR DOCTORAT LMD IN ORGANIC CHEMISTRY
OPTION
ORGANIC SYNTHESIS
TITLE
Reductive Removal of Trityl group
from Tetrazoles via Indium, Zinc and
Arene Catalyzed Lithiation
Under the suppervation of: Prof. Cherif. Behloul
Presented by: Bouchelouche Kenza
jury:
President: Dahmane. Tebbani
M.C.A. Univ. Freres Mentouri Constantine.
Supervisor: Cherif. Behloul Prof. Univ. Freres Mentouri
Constantine.
Examinateurs: Miguel. Yus Prof. Univ. Alicante
Alicante-Spain
Carmen. Nájera Prof. Univ. Alicante
Alicante-Spain
Dedication
Thanks to the Almighty, who gave me courage, the will, the force to
accomplish this memo , which no one cannot be made without its
desire.
I dedicate this modest work which I hope useful:
To My father to my tender and wonderful mother, I hope that they will
be always proud of me.
To my husband Fouad Abdennour who always supported me and has
greatly contributed to the success of this work.
To my little angel YASSER IYED.
To my brothers Yacine, Anis and my sister Karima
To my friends,
Acknowledgments
This work was accomplished in laboratory of the natural products of plant origin and organic synthesis (PHYSYNOR), Department of chemistry, Faculty of Exact Sciences, Univercity of Constantine (Algeria) and Department of organic chemistry, Univercity of Alicante (Spain).
First and foremost, I would like to thank my supervisor Prof. Cherif Behloul for giving me
the chance to conduct my Ph.D. work with him. He has always generously supported me and his wise guidance and his strong passion for science helped me to grow personally and professionally. Through out my stay, his belief and trust in my abilities allowed me to grow as a chemist and strengthen my confidence.
I also would like to express a special thanks to Dr. Dahmane Tebbani M. C. A at Univercity
of Constantine for its big assistant and for its advice which were always very precious. I would like to thank him for having honored me with chairing the jury of this thesis.
I would like to thank Prof. Miguel Yus of University of Alicante which has done me the honor
of participating in the commission of examination of this thesis. I would like to thank him for his expert opinion concerning my work and his valuable advaces on the content of publications produced in recent years.
I would like to address my special thanks to Ms. Carmen Nájera Professor at the University
of Alicante for having done me the honor to participate in Committee of examination of this thesis.
A special thanks to Professor David Guijarro for all his scientificl advices during my stay in
Alicante. Thanks for your help.
I would like to thank my dear friends: Aicha, Meriem, Wafa, Faiza, Zayneb who were always by my side, all the thanks words could not express my thanks and gratitude for their support to me.
Technical notes
During our work we used the following equipment:
Nuclear Magnetic Resonance spectrometry (NMR)
NMR spectra were recorded on a Bruker AC-300 spectrometer (300 MHz for 1H and 75 MHz for 13C) using CDCl
3, DMSO-d6, or CD3OD as solvent and TMS (δ= 0.00 ppm, 1H) or CDCl3 (δ= 77.0 ppm, 13C), DMSO-d6 (δ= 2.50 ppm, 1H; δ= 39.75 ppm, 13C), or CD3OD (δ= 4.87 ppm, 1H; δ= 49.0 ppm, 13C) as internal standards; chemical shifts are given in δ (ppm) and coupling constants (J) in Hz.
Multiplicities are given as s: singlet, d: doublet, t: triplet, td: triplet of doublet, m: multiplet, ddd: doublet of doublet.
Infra-Red spectrometry
FT-IR spectra were recorded on a Nicolet Impact 400D spectrophotometer using KBr pellets.
Melting points
All melting points were measured in open end glass capillary tubes on a Buchi 535 melting point apparatus and are uncorrected.
Chromatography
Column chromatography was performed on silica gel 60 (35–70 mesh) or basic aluminum oxide (50–160 μm particle size). Deactivated silica gel was treated with 5% Et3N in hexane, and the column was eluted with the same solvent mixture until the eluent was basic, as shown by pH paper.
1 3 4 4 5 5 5 6 6 6 8 8 9 9 10 10 10 11 12 12 13 13 15 16 16 16 17 17 18
Table of Contents
General introduction ReferencesChapter 1: The 5-Substituted Tetrazoles
Introduction
I.1. The 5-Substituted tetrazole I.2. Chemical and Physical Properties
I.2.1. Aromaticity
I.2.2. Tetrazolate anions: acidity I.2.3. Solubility
I.3. Medicinal Chemistry of Tetrazoles I.3.1. Action on central nervous system I.3.2. Anti-inflammatory activity
I.3.3. Derivatives with anti-allergic activity I.3.4. Cardiovascular activity
I.4. Synthesis of Tetrazoles
I.4.1. The Huisgen 1,3-dipolar cycloaddition
I.4.2. Synthesis of tetrazoles from nitriles with azides I.4.2.1. Neutral cycloaddition
I.4.2.2. Anionic mechanism I.4.2.3. Proton involvement
I.4.2.4. Hydrazoic acid
I.4.2.5. Metal salt methods using sodium azide
I.4.2.5.1. Ammonium and trialkyl ammonium azides I.4.2.5.2. NaN3 in the presence of Lewis acid
I.4.2.6. Sharpless methodology: The Click Chemistry approach I.4.2.6.1. The Click Chemistry
I.4.2.6.2. Synthesis of tetrazole rings I.4.2.7. Tin- and silicon-mediated methods
I.4.2.7.1. Trialkyltin azide I.4.2.7.2. Trimethylsilyl azide
18 19 20 21 21 22 22 23 23 24 25 25 26 26 26 27 28 36 37 42 42 43 44 46 47 48 48 49 49 50 50 I.4.2.7.2.1. TMSN3 under solvent free conditions
I.4.2.7.2.2. TMSN3 in the presence of dibutyltin oxide as catalyst I.4.2.7.2.3. TMSN3 in the presence of trimethyl aluminium
I.4.2.7.2.4. TMSN3 in the presence of Pd(PPh3)4: Yamamoto methodology I.4.2.8. Aluminum azide
I.4.2.9. Synthesis of 5-substituted tetrazoles using Zn/Al hydrotalcite catalyst I.4.3. Synthesis of tetrazoles with other methods
I.4.3.1. From N-(cyanoethyl)amides I.4.3.2. From oxime salts
I.4.3.3. From imidate salt and imidoyl chlorides I.5. Reactivity of Tetrazoles
I.5.1. Reaction with electrophiles
I.5.2. Alkylation of tetrazolate anion salts
I.5.3. Acylation and alkylation of neutral tetrazoles I.5.3.1. Michael reaction
I.5.3.2. Acylation I.6. Results and descussion I.7. Conclusion
I.8. Experimental part
Chapter 2: Protection of Tetrazole Ring
Introduction
II.1. Properties of a protective group II.2. Historical development
II.3. Development of new protective groups
II.4. The role of protecting groups in organic synthesis II.5. Protection of tetrazole ring
II.5.1. Chemical and Physical Proprieties of Disubstituted Tetrazoles II.5.1.1. Physical properties
II.5.1.2. Solubility and chromatography II.5.2. Alkylation of Tetrazole Ring
II.5.2.1. Alkylation of tetrazoles with Alkyl Halides II.5.2.2. Alkylation of tetrazoles with alcohols
51 51 52 52 53 53 54 54 56 61 62 70 71 71 74 74 75 76 76 77 79 80 82 91 92 100 100
II.5.2.3. Alkylation of tetrazoles by addition of C-C multiple bonds
II.5.3. Methylation of Tetrazole Ring
II.5.3.1. Methylation with dimethyl sulfate II.5.3.2. Methylation with methyl iodide II.5.3.3. Methylation with diazomethane
II.5.3.4. Methylation with trimethylsilyldiazomethane II.5.3.5. O-Alkyl-S-propargyl xanthates (dithiocarbonates) II.5.3.6. Synthesis of methyl-tetrazoles from imidates II.6. Results and discussion
II.7. Conclusion II.8. Experimental part
Chapter 3: Detritylation of protected tetrazoles by
naphthalene-catalysed lithiation
Introduction
III.1. Organolithium compounds from Non-Halogenated Materials III.1.1. Reductive Carbon-Oxygen Cleavage
III.1.2. Reductive Carbon-Nitrogen Cleavage III.1.3. Reductive Carbon-Sulfur Cleavage III.1.4. Reductive Carbon-Carbon Cleavage III.1.5. Reductive Deprotections
III.2. Preparation of Functionalized Organolithium Compounds III.2.1. Lithiation of Functionalized Halogenated Materials III.2.2. Lithiation of Functionalized Sulfur Derivatives III.2.3. Reductive Opening of Heterocycles
III.3. Results and discussion III.4. Conclusion
III.5. Experimental part
Chapter IV: Indium-mediated Cleavage of the Trityl Group
from Protected 1H-Tetrazoles
Introduction
100 100 101 102 102 103 103 104 104 105 105 107 107 107 108 108 108 109 109 110 110 111 111 113 115 116 122 122 123 124
IV.1.1. Allylation and Vinylation Reactions IV.1.1.1. Regioselective Allylation of Alkynes IV.1.1.2. Allylation of Aldehydes
IV.1.1.3. Allylation of Ketones
IV.1.1.4. Allylation of β-Keto Phosphonates IV.1.1.5. Vinylation of β-Keto Esters IV.1.2. Coupling Reactions
IV.1.2.1. Reactions of Alkyl Halides IV.1.2.2. Reactions of Alcohols
IV.1.3. Addition and Condensation Reactions IV.1.3.1. Addition of Carbonyl Compounds
IV.1.3.2. Mannich-Type Condensations of Aldimines IV.1.4. Synthesis of Heterocycles
IV.1.4.1. Synthesis of Phenanthridines
IV.1.4.2. Synthesis of Benzo-Fused Heterobicycles from D-Glucal IV.1.5. Miscellaneous Reactions
IV.1.5.1. Stereoselective Debromination of vic-Dibromides IV.1.5.2. Reduction of Hydroxylamines to Amines
IV.1.5.3. C-Alkylation of Indoles
IV.1.5.4. Cleavage of tert-Butoxycarbonyl Groups
IV.1.5.5. Oxidative Cleavage of C-C Multiple Bonds by tert-Butyl Hydroperoxide .. IV.1.5.6. Deprotection of trichloroethoxycarbonyl and trichloroacetyl groups
IV.1.5.7. Reduction of Carbon-Halogen Bonds IV.2. Results and discussion
IV.3. Conclusion IV.4. Experimental part
Chapter V: Detritylation of protected Tetrazoles by
Dissolving Zinc-Metal
Introduction
V.1. Reduction of Carbon-Carbon Multiple Bonds V.2. Reduction of Carbonyl Groups
124 125 125 125 126 127 127 128 128 128 130 132 133 139 140 169 V.4. Reduction of Carbon-Halide Bonds
V.5. Reduction of Carbon-Nitrogen bonds V.6. Reduction at Heteroatoms
V.6.1. Dehalogenation and Related reaction V.6.2. The Reformatsky Reaction
V.7. Dissolving metals
V.7.1. Reduction of Imines V.7.2. Reduction of Sulfoxides
V.7.3. Protecting groups cleaved by dissolving metal reduction V.7.4. Reduction with Zinc
V.8. Results and discussion V.9. Conclusion V.10. Experimental part General Conclusion Résumé de la thèse References Annex
General Introduction
1
General Introduction
Tetrazoles are a class of heterocycles with a wide range of applications in medicinal chemistry and in material sciences. However, Sartans are a group of drugs that are effective in treating hypertension and heart failure. They block the renin-angiotensin system and they are among the most effective treatments for hypertension.1
Of the seven sartans that are used in clinical practice, five contain tetrazole moieties within their structures. The protection and deprotection of the nitrogen atom of the tetrazole ring is a crucial operation during the synthesis of these sartans.2
One group that can be used to protect the tetrazole nitrogen is the triphenylmethyl (trityl) group, a very efficient protecting group for amines3 and amino acids,4 because its bulkiness causes the nitrogen atom to be much less reactive as a nucleophile. Simple treatment with an aqueous acidic solution can be used to remove the trityl protecting group,3c but some side-reactions have been observed under these conditions, such as elimination of tritylamine during detritylation of some tritylated amines.5 Other procedures that have been shown to be efficient in detritylation processes include dissolving-metal reduction,3c reactions with molecular hydrogen catalyzed by palladium,3c reduction with sodium borohydride in the presence of mercury salts,6 and reductive cleavage promoted by silanes7 or low-valent titanium reagents.8 Palladium catalysts in combination with poly(methylhydrosiloxane) have been shown to permit direct conversion of N-trityl amines into tert-butyl carbamates.9
The aim of this project is developing new methods to remove trityl unit from the nitrogen atom of several protected tetrazoles.
This project is composed of two essential parts as follows:
Part one concludes the introduction and presenting the importance of the heterocyclic compounds that contain tetrazole skeleton. Also this part is concluded from the point of view; synthesis, reactions and biological activities of tetrazoles and protected tetrazoles, after that we report the development of two novel efficient processes one for transforming a wide variety of nitriles into the corresponding tetrazoles in high yield, using a simple and safe protocol. And the other one is to protect tetrazoles wich is our starting materials.
Part two concludes our research of developing deprotection methods to remove the trityl group from the nitrogen atom of several protected tetrazoles using different electron transfer sources (lithium, indium and zinc). See the following general scheme below.
General Introduction
2
General Introduction References
3
References
1. For example, see: Applegate, H. E.; Cimarusti, C. M.; Dolfini, J. E.; Funke, P. T.; Koster, W. H.; Puar, M. S.; Slusarchyk, W. A.; Young, M. G. J. Org. Chem. 1979, 44, 811.
2. Srimurugan, S.; Suresh, P.; Babu, B.; Hiriyanna, S. G.; Pati, H. N. Chem. Pharm. Bull.
2008, 56, 383.
3. a) Sheppard, R. C. In Comprehensive Organic Chemistry, Vol. 5; Barton, D.; Ollis, W. D., Eds.; Pergamon Press: Oxford, 1979, 323. b) Kunz, H.; Waldmann, H. In
Comprehensive Organic Synthesis, Vol. 6; Trost, B. M.; Fleming, I., Eds.; Pergamon
Press: Oxford, 1991, p. 644. c) Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis; John Wiley & Sons: New York, 1999, 583.
4. a) Bodanszky, M.; Onetti, O. A. Peptide Synthesis; Interscience: New York, 1966, 36. b)
Bodanszky, M. Principles in Peptide Synthesis, 2nd Ed.; Springer-Verlag: New York,
1993, p. 88.
5. See, for instance: Sharma, S. K.; Songster, M. F.; Colpitts, T. L.; Hegyes, P.; Barany, G.; Castellino, F. J. J. Org. Chem. 1993, 58, 4993.
6. Maltese, M. J. Org. Chem. 2001, 66, 7615.
7. Vedejs, E.; Klapars, A.; Warner, D. L.; Weiss, A. H. J. Org. Chem. 2001, 66, 7542.
8. Rele, S.; Nayak, S. K. Synth. Commun. 2002, 32, 3533.
Chapter 01: The 5-Substituted
Tetrazoles
Chapter I The 5-Substituted Tetrazoles
3
Introduction
Tetrazoles are a class of heterocycles with a wide range of applications which are currently receiving considerable attention,1 therefore the literature on tetrazole is expanding rapidly. This functional group has a role in coordination chemistry as a ligand,2,3,4 as well as in various materials sciences applications including photography and specialty explosives.5 Extensive work has also been carried out in the field of medicinal chemistry, where tetrazoles are frequently used as metabolically stable surrogates for carboxylic acids.6,7,8
Less appreciated, but of enormous potential, are the many useful transformations that make tetrazoles versatile intermediates en route to substituted tetrazoles and especially to other 5-ring heterocycles via Huisgen rearrangement.9,10 The prime reason for the scarcity of practical applications for these sophisticated tetrazole-based reactions is the lack of appealing synthetic routes to the key intermediates 5-substituted tetrazoles. Tetrazoles readily tolerate a wide range of chemical environments1 and new uses for this unique family of heterocycles continue to emerge in both materials science, and pharmaceutical applications.
I.1. The 5-Substituted Tetrazoles
5-Substituted tetrazoles that contain a free N-H bond are frequently referred to as tetrazolic acids and exist in two tautomeric forms (Figure 1).1, 11,12
Figure 1. Tetrazolic acids are bioisosteres of carboxylic acids.
The tautomerism is a rapid process in solution and individual tautomers can not be detected even at low temperature. The corresponding dipole moments are 5.63 D for the 1H-tautomer and 2.19 D for the 2H-form.1 In the gas phase, the 2H-tautomer tends to be the dominant form, while in solution the 1H-tautomer is favored because of solvation effects.
Tetrazoles can be regarded as nitrogen analogues of carboxylic acids. The free N-H bond of tetrazoles makes them acidic molecules and both the aliphatic and aromatic heterocycles have pKa values similar to the corresponding carboxylic acids (4.5-4.9 vs
4.2-Chapter I The 5-Substituted Tetrazoles
4
4.4, respectively) due to the ability of the moiety to stabilize a negative charge by electron delocalization.1
Tetrazole nitrogens have a considerable amount of local electron density, which consequently leads to a wide range of stable metallic and molecular complexes.13 Furthermore, the tetrazole ring possesses a strong electron-withdrawing inductive effect (-I) which surpasses the weak mesomeric effect (+ M), therefore, the ring is a deactivating group.1
I.2. Chemical and Physical Properties
I.2.1. Aromaticity
The tetrazole ring is a 6π-azapyrrole-type system.1,11 Reactivity of 5-substituted tetrazoles permits them to be classified as aromatic compounds.1,14 In tetrazoles, two of the six π-electrons required by the Huckel rule are provided by the lone pair of one nitrogen while the remaining four π-electrons are provided by the other four atoms of the ring.
I.2.2. Tetrazolate anions: acidity
5-Substituted tetrazoles display an acidity comparable with the corresponding carboxylic acids.1,15 One difference between the tetrazole ring and the carboxylic acid group is the annular tautomerism of the tetrazoles. Substituents at C-5 have effects similar to those for carboxylic acids, while in general, 5-aryltetrazoles 1 are stronger acids. The increased
acidity is ascribed to an enhanced resonance stabilization in the 5-phenyltetrazole anion 2
relative to benzoate.1b The tetrazolate anions are easily generated with metal hydroxides and are stable in hot alcoholic and aqueous solutions (Figure 2).16,1
Chapter I The 5-Substituted Tetrazoles
5
I.2.3. Solubility
5-Substituted tetrazoles are generally soluble in polar organic solvents such as ethyl acetate and DMSO, but under basic conditions they can be easily extracted into the water phase as a salt, like the carboxylic acid. Very polar tetrazole derivatives such as pyridinetetrazoles 3, 4 and 5 or pyrrolidine tetrazoles 6 are soluble in water therefore the
extraction from water can be problematic (Figure 3).
Figure 3.
I.3. Medicinal Chemistry of Tetrazoles
Tetrazoles are an increasingly popular functionality with wide ranging application. They have found use in coordination chemistry16,17 and in various materials sciences applications including photography,1,18 specialty explosives,5 information recording systems19 and agricultural composition.20 In addition extensive work has been carried out in the field of medicinal chemistry.1,9
I.3.1. Action on central nervous system
Several tetrazole derivatives act on the central nervous system, the most prominent being compounds reported to possess analeptic activity. The standard drug in the area is leptazol (pentamethylenetetrazole) 7. Leptazol produces hypothermia and this effect is
probably the result of a direct effect of the drug on the thermoregulaiory mechanism in the hypothalamus, and not necessarily mediated by the release of a neurohumoral substance from the hypothalamus.21 Leptazol was recommended as a more sensitive tool for detecting potential anti-convulsants.22 Tetrazole derivatives possessing a methyl or ethyl group at position 5 and a substituent at position 1 having four to six carbon atoms are active as analeptics, 23 the more significant activity is obtained when 1,5-positions are bridged through a penta- or hepta-methylene chain.24 An increase25 or decrease26 in the number of polymethylene carbons is not conducive for the activity. However, tetrazoles prepared from
Chapter I The 5-Substituted Tetrazoles
6
camphor and α-thujone and mixtures of α- and β-thujone are reported to be active analeptics.27 „Camphor tetrazole‟ is claimed to be very potent in drogs,28 and l-isobornyld-methyltetrazole is also reported to be active29 (Figure 4).
Figure 4.
The effect of substitution on carbons of pentamethylene bridge in 7 has also been
examined.23 The 8-methyl 8, 8-isopropyl 9 and 8-tert-butyl 10 derivatives were more potent than 7 whereas there was drop in activity in the 8-sec-butyl or tert-pentyl analogues. The spiro
analogue 11 was also claimed to be more active analeptic than 7.30 The analeptic activity of 7 was lost on quaternary salt formation.23 The monochloro and dichloro substitution at position 6 in 7 increased the activity;24 however, the bromo analogues were less active.
Of the actions of several other tetrazole derivatives showing central nervous system activity tetrazole analogues 12,31 13 and 14.32 However, 1,3-dihydro-1-methy1-7-(2-methyltetrazol-5-y1)-5-phenyl-2H-1, 4-benzodiazepin-2-one 15 and
1,3-dihydro-1-methy1-7-(1-methyltetrazol-5-yl)-5-phenyl-2H-1,4-benzodiazepin-2-one 16 were found to be inactive as
sedative and anti-convulsants33 (Figure 5).
Chapter I The 5-Substituted Tetrazoles
7
I.3.2. Anti-inflammatory activity
Maximum anti-inflammatory activity was found in those members of the series which have meta-halogenated aromatic substituents and a propionic acid residue at position 2 of the tetrazole ring 17. The amides obtained from the corresponding acids have also been found to
be active.34 The quantitative structure-activity relationship in the series has been studied.35 Substituted benzylidene derivatives 18 of 2-hydrazinocarbonylmethyl-5-phenyltetrazole are
also reported to be active.36 In addition, certain carbamido derivatives 19 are active as anti-inflammatory agents37 (Figure 6).
Figure 6.
I.3.3. Derivatives with anti-allergic activity
Several 3-(tetrazol-5-yl)chromones have been reported to be active as antiallergic.38 In contrast to inactivity of 20,38 the tetrazole derivative 21 was active.38 The inactivity of former was attributed to its weak acidity due to intra-molecular hydrogen bonding. In general, the analogues bearing a tetrazole group at C-3 were 2.5 times as active as compared with C-2 tetrazole-substituted chromones . The derivatives of 21 with substitutions at 6 and 8 positions
were even more active (Figure 7).
Figure 7.
There are several other patents39 of assorted types of tetrazole derivatives which are claimed to possess anti-allergic activity. Among them may be mentioned the compounds 2239 and 2340 (Figure 8).
Chapter I The 5-Substituted Tetrazoles
8
Figure 8.
I.3.4. Cardiovascular activity
The 5-(4‟-methyl-1,1‟-biphenyl-2-yl)-tetrazole subunit has been used as a carboxylic acid mimic in the class of so called sartan derivatives (Figure 9). Angiotensin II (AII) is the
octapeptide responsible for the peripheral effects of the rennin-angiotensin system43,44,45,46,47 which include the regulation of blood pressure and volume homeostasis. Lorsartan was the first nonpeptide angiotensin receptor antagonist to appear on the market41,42,44,48 followed by Valsartan (Figure 9). The 5-(4‟-methyl-1,1‟y-biphenyl-2-yl)-1H-tetrazole subunit has become
ubiquitous in the most potent and bioavailable antagonists disclosed to date.31
Figure 9. Sartans.
I.4. Synthesis of Tetrazoles
5-Substituted tetrazoles are usually obtained by the addition of azide ion to organic nitriles and many methods are reported in the literature.1,8,49,50,51 Unfortunately, each of those protocols suffers from some disadvantages: the use of both toxic metals and expensive reagents, drastic reaction conditions, water sensitivity and possible presence of dangerous hydrazoic acid or other explosive sublimates.
Chapter I The 5-Substituted Tetrazoles
01
I.4.1. The Huisgen 1,3-dipolar cycloaddition
The Huisgen 1,3-dipolar cycloaddition is the reaction of alkynes to azides to form 1,4-disubsituted-1,2,3-triazoles (Scheme 1).9 A notable variant of the Huisgen cycloaddition is the copper (I) catalyzed variant, in which organic azides and terminal alkynes are united to afford 1,4-regioisomers of 1,2,3-triazoles as sole products.52 Huisgen was the first to understand the scope of this organic reaction. This cycloaddition is considered the cream of the crop of “click chemistry”. The azide and alkyne functional groups are largely inert towards biological molecules and aqueous environments, which allows the use of the Huisgen 1,3-dipolar cycloaddition in target guided synthesis53 and activity-based protein profiling.54 The resulting triazole has similarities to the ubiquitous amide moiety found in nature, but unlike amides, is not susceptible to cleavage.
Scheme 1. Huisgen 1,3-dipolar cycloaddition of alkynes to azides.
I.4.2. Synthesis of tetrazoles from nitriles with azides
Tetrazoles are generally prepared by the reaction of a hydrazoic acid source with a nitrile, in an inert solvent at high temperatures. They fall into three main categories: those that make use of tin or silicon azides, those that use strong Lewis acids55,56 and those that are run in acidic media.57 The few methods that seek to avoid hydrazoic acid liberation during the reaction by avoiding acidic conditions, require a very large excess of sodium azide.58 In addition, all of the known methods use organic solvents, in particular, dipolar aprotic solvents such as DMF. This is one of the solvent classes that process chemists would rather not use. The mechanism of the reaction of azide salts to nitriles is different for different azide species59,60,61 and several possible reaction pathways can be envisioned.62,63,64
I.4.2.1. Neutral cycloaddition
A [2+3] cycloaddition is the most likely pathway for the bimolecular addition of non-ionic azides to nitriles.61 In concerted cycloadditions, two different isomers of tetrazole, the
Chapter I The 5-Substituted Tetrazoles
00
1,5- and the 2,5-disubstituted, can be formed. Generally the TS1 is the preferred transition state using electron-withdrawing substituents R (Scheme 2).
Scheme 2. Neutral cycloaddition.
I.4.2.2. Anionic mechanism
In reactions where NaN3 is added to nitriles in aprotic organic solvents, such as dimethylformammide (DMF), it has been found that yields are generally lower and higher temperature are required.57,62 In theses cases, there are two possible mechanisms,61 either a direct [2+3] cycloaddition or a two step-mechanism sequence wherein the azide first nucleophilically attacks the nitrile, followed by ring closure. In this context, Sharpless et al. have calculated the barriers of cycloaddition of the azide anion to nitrile.61 As in the case of the neutral [2+3] cycloadditions, the barrier for anionic [2+3] cycloaddition decreases with increasing electron-withdrawing potential of the substituent on the nitrile. The geometry of the transition state of anionic reactions is more asymmetric than for neutral reactions. The Cnitrile-Nazide distance is significantly shorter than the Nnitrile-Nazide distance. The difference grows with the withdrawing potential of the substituent and for very strong electron-withdrawing groups like RSO2, an intermediate such as that shown in Figure 10 could be found. Despite the existence of this intermediate for the strongly activated nitriles, the G≠ of the transition state for the ring closing turns out to be identical to the G≠ for concerted [2+3] transition state. The two pathways have therefore essentially the same rate.61
Chapter I The 5-Substituted Tetrazoles
01
Figure 10.
I.4.2.3. Proton involvement
Koldobskii et al.65 showed that protic ammonium salts of azide are competent dipoles; tetrabutylammonium azide does not work. When a proton is available, the nitrile is activated and the reaction is supposed to proceed via an intermediate instead of a direct [2+3] dipolar cycloaddition (Scheme 3).61
Scheme 3.
I.4.2.4. Hydrazoic acid
The acid-catalysed cycloaddition between hydrazoic acid and nitriles has long been one of the main routes to 5-substituted tetrazoles.8,66 The first method to appear in the literature was the reaction of hydrazoic acid (HN3) with organic cyanides in 1932.67 This process is generally thought to occur by a concerted 1,3-dipolar cycloaddition mechanism, in which the nitrile acts as the dipolarophile toward the azide, which serves as the 1,3-dipolar species in the cycloaddition. Protonation of the tetrazolium anion upon workup provides the tetrazolic acid. In literature a two-step mechanism has also been reported.68 However this standard procedure needs the direct addition of a large excess of dangerous and harmful hydrazoic acid. Hydrazoic acid itself is poisonous, extremely explosive, and has a low boiling point (37°C). Not many organic solvents are stable at the high temperatures that are necessary for this cycloaddition (sometimes as high as 130°C), and for this reason DMF is most commonly used for this purpose.1,29
Chapter I The 5-Substituted Tetrazoles
02
I.4.2.5. Metal salt methods using sodium azide
I.4.2.5.1. Ammonium and trialkyl ammonium azides
The reaction of nitriles with the ammonium and trialkyl ammonium azides in organic solvents such as dimethylformamide, has been found fifteen years ago by Lofquist and Finnegan62 to be a general method to give good yields of 5-substituted tetrazoles. The reactive azide species is prepared in situ by reaction of sodium azide and the appropriate ammonium or trialkyl ammonium chloride (Scheme 4). The proposed mechanism involves a nucleophilic
attack of azide ion on the carbon of the nitrile group, followed by ring closure of the imino azide to form the tetrazole ring.62 Electronegative substitution on the nitrile enhances the rate of the reaction. The solubility of the azide salt also influences the rate of reaction. The ammonium azides are soluble in dimethylformamide.
Scheme 4. Synthesis of 5-phenyltetrazole with ammonium azide.
This methodology is not appropriate for the preparation of 5-thiosubstituted tetrazoles because they easily undergo irreversible decomposition to hydrazoic acid and thiocyanate at or near their melting points, which are, in several cases, quite close to the reflux temperature of DMF;69 therefore using high temperature is not advisable in these cases. In addition this protocol for the synthesis of tetrazole rings is accompanied by the sublimation of explosive NH4N3.70 The sublimation of explosive NH4N3 also occurs when other aprotic solvents instead of the DMF are used for the reaction.
Bernstein and Vacek showed that a combination of sodium azide and triethylammonium chloride is an useful alternative to synthesize tetrazoles when N-methylpyrrolidinone is used as a solvent instead of the DMF (shorter reaction times) (Scheme 5).71 DMF under heating and basic conditions partially decomposes and forms free nucleophilic amines which may react with starting nitriles which contain certain functional groups.71 An alternative to eliminate the amine sources was found to be the use of 1-methyl-2-pyrrolidinone as solvent.
Chapter I The 5-Substituted Tetrazoles
03
Scheme 5. Preparation of 5-substituted tetrazoles.
Koguro et al., reported a variant by using triethyl amine hydrochloride in toluene.72 In this procedure, the authors proposed that the intermediate complex [Et3N・HN3] is first ionized as Et3NH+ and N3-, then, each of these react with the triple bond of the nitrile group to produce 28 (Scheme 6). When an aromatic solvent such as toluene is used, both the cation
and the anion are not solvated, and the reaction thus proceeds smoothly.
Scheme 6. Synthesis of tetrazoles with triethylammonium azide.
LeBlanc and Jursic recently reported a simple alternative for the method using sodium azide and ammonium chloride in DMF, by working under phase transfer conditions (PTC)
(Scheme 7).73 Hexadecyltrimethylammoniumbromide was found to be the most useful catalyst. The ratio of water and toluene as well as the reaction temperature are important factors to obtain satisfactory yields. This methodology can be a good alternative to the simple use of sodium azide and amonium chloride69 for the preparation of alkylthio and 5-arylthiotetrazoles, which are activators for RNA and DNA synthesis. However this procedure requires long reaction times, which makes an application in an industrial scale up improbable.
Chapter I The 5-Substituted Tetrazoles
04
Scheme 7. Synthesis of tetrazoles using PTC conditions.
I.4.2.5.2. NaN
3in the presence of Lewis acid
Finnegan and Lofquist reported in 1958 the study of the tetrazole formation in the presence of Lewis acids.62 The proposed mechanism involves a nucleophilic attack of the azide ion on the carbon of nitrile group, followed by ring closure of the imino azide to form the tetrazole ring. Conditions which enhance or favour a δ+ charge on the nitrile carbon, such as the cordination of a Lewis acid, increase the rate of the reaction (Scheme 8).
Scheme 8. Tetrazole formation in the presence of Lewis acid.
Nearly four decades later Shechter et al. reported the preparation of a few simple 5-(hydroxy-phenyl)tetrazoles by the addition of aryl nitriles with sodium azide in the presence of boron trifluoride (Scheme 9).74
Scheme 9. Preparation of tetrazoles with NaN3 in the presence of BF3 as Lewis acid. Recently the use of aluminum chloride as a Lewis acid catalyst for the generation of aliphatic tetrazoles with a relatively low yield has been reported.75 The crude was protected as a resin-bound trityl derivatives, which was subjected to alkylation followed by cleavage from the solid support to generate the desired tetrazole derivatives (Scheme 10).
Chapter I The 5-Substituted Tetrazoles
05
Scheme 10. Tetrazole ring formation with NaN3 in the presence of AlCl3 as Lewis acid.
I.4.2.6. Sharpless methodology: The Click Chemistry approach
I.4.2.6.1. The Click Chemistry
The term “Click Chemistry“ was introduced by K. Barry Sharpless et al. in 2001.76,77 “Click chemistry” is a modular approach that uses only practical and reliable reactions with readily available reagents. In several instances water is the ideal reaction solvent, providing the best yields and highest rates. Reaction work-up and purification uses benign solvents and avoids chromatography.
One of the “click approaches” is the copper-(I)-catalyzed 1,2,3-triazole formation from azides and terminal acetylenes as a particularly powerful linking reaction, due to its high degree of reliability and complete specificity of the reactants.
I.4.2.6.2. Synthesis of tetrazole rings
Sharpless et al. have reported a simple protocol for transforming a wide variety of nitriles into the corresponding 1H-tetrazoles, by using NaN3 in the presence of Zn(II) salts in aqueous conditions (Scheme 11).61,63,78,79 This procedure shows a good level of generality, however, in the case of sterically hindered aromatic or alkyl inactivated nitriles, high temperatures (140-170°C) are required. They have not been able to achieve significant conversions of aromatic nitriles bearing an sp3-hybridized substituent in the ortho position.63 When the reaction is run at a concentration of (1 M) in sodium azide and (1 M) of ZnBr2 a small amount of hydrazoic acid in the headspace above the reaction mixture is liberated.78 Even at 100°C, release of hydrazoic acid is minimal. The exact role of zinc is not yet clear.78
Chapter I The 5-Substituted Tetrazoles
06
The mechanism of the reaction has been controversial, with evidence supporting both a two-step mechanism and a concerted [2+3] cycloaddition.61
Scheme 11. Tetrazole ring formation with the Sharpless methodology.
The chief competing reaction is hydrolysis of the nitrile to primary amide; therefore with electron-poor nitriles, lowering the amount of zinc avoids significant formation of the amide byproduct. Other zinc salts such perchlorate and triflate also work; Zinc bromide is the best compromise between cost, selectivity and reactivity.
I.4.2.7. Tin- and silicon-mediated methods
Some of the newer methods for the preparation of 5-substituted tetrazoles involve the reaction of alkyl- or arylnitriles with safer organic soluble azides such as trialkyltin azide or trimethylsilylazide.29,1,80
I.4.2.7.1. Trialkyltin azide
Methods for the tetrazole formation from organic-soluble reagents trimethylstannyl81 or tri-n-butylstannyl azides48,82 are more commonly utilized in larger scale than the sodium azide /ammonium salt protocols.
Duncia and Carini,44 of DuPont, looking for a good alternative method to synthesize sartans83 and using the biphenylnitrile 34 as a model system, discovered that both trimethyl- and n-butyltin azides react forming the trialkltin-tetrazole adducts. However, removal and disposal of stoichiometric (highly toxic) residual organotin at the end of the reaction is a major drawback of this methodology.48
Trialkyltin azide is typically prepared in situ from trialkyl chloride (volatile and toxic) and sodium azide, and has been shown to be effective in the synthesis of 5-substituted tetrazoles. Better yields are generally obtained compared to silicon-based azide reagents. The treatment of the starting nitrile 34 with trimethyl- or tri-n-butyltin azide48 in toluene or xylene at refluxing gives the corresponding tetrazole. The insoluble tin-tetrazole adduct 35
Chapter I The 5-Substituted Tetrazoles
07
precipitates and when the reaction is finished, the product is simply filtered and dried. Subsequent acid hydrolysis yields the desired tetrazole (Scheme 12).
Scheme 12.Synthesis of sartans precursor using trimethyltin azide.
Higher temperature and/or longer reaction time are required using tri-n-butyltin reagent because of the more bulky character. An alternative to remove the tributyltin moiety, is to substitute the tin group with a trityl protecting group.
I.4.2.7.2. Trimethylsilyl azide
Trimethylsilyl azide has been reported to react with nitriles to give 5-substituted tetrazoles. 84 It is an attractive azide source due to its stability and relatively high boiling point (105°C). However, benzonitrile reacts with only very low conversion and ortho-substituted benzontriles fail to undergo the reaction.
I.4.2.7.2.1. TMSN
3under solvent free conditions
Pizzo et al. recently reported the use of TMSN3 in solvent free conditions.85 Catalytic amount of tetrabutylammonium fluoride (TBAF) is used for the anionic activation of the silicon-nitrogen bond.86 The use of TBAF has the advantage to activate the azide nucleophile and deprotects the N-silylated products. This catalytic system is relatively efficient and a wide range of tetrazoles are obtained in 1 to 48 hours at 85 to 120°C (Scheme 13).
Chapter I The 5-Substituted Tetrazoles
08
I.4.2.7.2.2. TMSN
3in the presence of dibutyltin oxide as catalyst
The use of trimethlsilyl azide in the presence of a catalytic amount of dibutyltin oxide to convert nitriles into tetrazoles has been developed (Scheme 14).43,87 ,88
Scheme 14. Synthesis of tetrazoles with TMSN3 in the presence of dibutyltin oxide as Catalyst.
In the general procedure the nitrile is treated in toluene at high temperature for 24 to 72 hours, with 2 equivalents of trimethylsilyl azide and 0.1 equivalent of dibutyltin oxide to provide the desired tetrazole. However in some cases, full conversion is obtained using in total 1 equiv of tin reagent and 5 equiv of (TMS)N3 at 100°C (Scheme 14).
The catalytic cycle involves the formation in situ of the dialkyl(O-trimethylsilyl) azidostannylhydrin 42 which reacts with the nitrile to give the N-(dialkyl
(trimethylsloxy)stannyl)tetrazole 43 (Scheme 15). The intermediate N-(dialkyl(trimethylsoloxy)stanyl)tetrazole 33 breaks down into the N-(trimethylsilyl)tetrazole 40 and the dialkyltin oxide 41 that carries on the catalytic cycle (Scheme 15).43
Chapter I The 5-Substituted Tetrazoles
11
Scheme 15.
The trimethylsilyl azide as the azide source greatly reduces the hazard posed by in situ generation of hydrazoic acid and eliminates the possibility of the exposure to the toxic trialkyltin chloride used for the preparation of trialkyltin azide. However, at least two equivalents of trimethylsilyl azide are required for the reaction to run to completion and it is still difficult to separate the desired product from the stannane compounds. In addition the stannane compounds used in these reactions are generally highly toxic and require additional treatment of the waste water.
I.4.2.7.2.3. TMSN
3in the presence of trimethyl aluminium
A method using trimethylsilyl azide was recently described by Lilly chemists Huff and Staszak,55 who showed that an equimolar mixture of trimethylaluminum and trimethylsilyl azide in hot toluene is an efficient combination to prepare 5-substituted tetrazoles (Scheme 16). However, highly hindered nitriles resulted in poor conversion and the results are similar
to those obtained using n-Bu3SnN3.
Roeder and Dehnicke89 reported that trimethylaluminum when treated with trimethylsilyl azide forms a 1 to 1 complex at temperatures below 120°C which reacts to give
Chapter I The 5-Substituted Tetrazoles
10
(Me2AlN3)3 only at higher temperature. Therefore, it is likely that trimethylaluminum simply acts as a Lewis acid under these reactions and does not form (Me2AlN3)2.
Scheme 16. Synthesis of tetrazoles with TMSN3 in the presence of Me3Al.
I.4.2.7.2.4. TMSN
3in the presence of Pd(PPh
3)
4: Yamamoto methodology
Yamamoto et al. reported the synthesis of 2-allyltetrazoles starting from cyano compounds via the palladium-catalyzed three-components coupling reaction.90 The N-silyl tetrazole 48, derived from the cycloaddition reacts in situ with the π-allylpalladium species to
provide the N-allylated product 48 (Scheme 17).
Scheme 17. Preparation of 2,5-disubstituted tetrazoles.
I.4.2.8. Aluminum azide
Aluminum azides have already been reported by Wiberg and Michaud in a 1957 German patent.91 The Al(N
3)3 can be prepared by treatment of AlCl3 with 3 equivalents of NaN3 in THF at reflux.91,92 However, using aluminum azide for the preparation of tetrazoles,
Chapter I The 5-Substituted Tetrazoles
11
two moles of HN3 are formed for every mole of product during the acidic quench of the reaction. The mechanism proposed proceeds through intramolecular delivery of N3- from Al(N3)3 complexed with the nitrile (Scheme 18).
Scheme 18. Proposed mechanism fort the tetrazole formation with Al(N3)3.
I.4.2.9. Synthesis of 5-substituted tetrazoles using Zn/Al hydrotalcite catalyst
Katam et al. reported an alternative method to prepare tetrazole rings using Zn/Al hydrotalcite as heterogeneous catalyst93 (Scheme 19). The anionic [Zn-Al-Cl], with [Zn]/[Al] ratio of 3 to 1, is synthesized by co-precipitation at pH 9. This methodology requires relative high temperature and long reaction times in DMF, with the use of Zn which requires additional treatment of the waste water.
Scheme 19. Zn/Al hydrotalcite catalyzed synthesis of 5-substituted-tetrazoles.
I.4.3. Synthesis of tetrazoles with other methods
Several reports have appeared which make use of precursors other than nitriles to prepare 5-substituted-1H-tetrazoles. Short overviews of these methods are given herein.
Chapter I The 5-Substituted Tetrazoles
12
I.4.3.1. From N-(cyanoethyl)amides
N-(Cyanoethyl)amides 50 reacts with trimethylsilyl azide to provide 1N-protected
tetrazole 52 (Scheme 20). Removal of the N-cyanoethyl moiety of 52 with aqueous sodium
hydroxide, followed by acidification, led to the free tetrazole 53 in relative good overall yield (Scheme 20).8
Scheme 20.
I.4.3.2. From oxime salts
An useful process for the preparation of 5-substituted-tetrazoles is the reaction of oxime salt 55 with sodium azide developed by Antonowa and Hauptmann.94 In this procedure, benzaldehyde 54 may be directly transformed into the corresponding aryl tetrazole 56 (Scheme 21).
Chapter I The 5-Substituted Tetrazoles
13
I.4.3.3. From imidate salt and imidoyl chlorides
Zard et al. proposed an alternative method to prepare 5-substituted tetrazoles from imidate salts which does not involve azides.95 The reaction of imidates 57 with N-formyl hydrazine is known to give 1,2,4-triazoles via the intermediate N-formyl amidrazones 58.
However, by working at low temperature (0°C) the triazole formation can be avoided and indeed, in the presence of sodium nitrite and diluted HCl, the desired tetrazole 61 can be
isolated in good yields (Scheme 22). The triazole 60 can be isolated only upon heating in
xylene.
Scheme 22.
Few years later, Zard96 proposed a method to prepare disubstituted tetrazoles. The reaction of imidoyl chloride 62 with sodium azide provides the 5-chloro methyl tetrazole 63
which is then treated with potassium O-ethyl xanthate in acetone to give the corresponding tetrazole xanthates 64 (Scheme 23).
Chapter I The 5-Substituted Tetrazoles
14
Koldobskii et al. proposed the synthesis of 1,5-disubstituted tetrazoles under phasetransfer conditions from imidoyl chlorides by treatment with sodium azide
(Scheme 24).97
Scheme 24.Synthesis of tetrazoles from imidoyl chlorides.
I.5. Reactivity of Tetrazoles
Reactivity of 5-substituted tetrazoles permits to classify them as aromatic compounds. The ring undergoes electrophilic substitution, is stable toward oxidation and, in general, the tetrazole ring remains unchanged during reduction of susceptible substituents.1
I.5.1. Reaction with electrophiles
Peculiarities of the π-electron system of the tetrazole ring is the availability of lone pairs of the nitrogens which allow these heteroatoms to be attacked by various electrophilic reagents.1,98 Aside from the variety of alkyl substituents, many other groups can be introduced including acyl, imidoyl, silyl, phosphoryl, sulfonyl, aryl, vinyl and amino functions.98
The most common nucleophile type reactions at the tetrazole nitrogens arise from the acidity of the ring N-H bond. The tetrazolic acids form stable anions when treated with bases and are more reactive than neutral tetrazoles towards electrophiles and alkylating agents
(Scheme 25).98 The product is a mixture of 1N- and 2N-alkyl isomers, the relative proportions of which depend upon the conditions of the alkylation, the steric requirements of the alkylating agent and the influence of the 5-substituent. In general, electron-donating substituents at C-5 tend to favor 2N-alkylation.
Chapter I The 5-Substituted Tetrazoles
15
Scheme 25. Reactions with electrophiles.
I.5.2. Alkylation of tetrazolate anion salts
Metal salts of 5-substituted tetrazoles undergo to alkylation on heating with alkyl halides in a wide range of solvents. The products are a mixture of 5-substituted 1N- and 2N-alkyl tetrazoles (Scheme 26).1
Scheme 26.
I.5.3. Acylation and alkylation of neutral tetrazoles
There are a variety of electrophilic substitutions on 5-substituted tetrazoles with reagents such as hydrazonoyl halides, electron-deficient vinyl systems and acyl halides.49 These reactions are carried out in the presence of excess Et3N used to promote loss of halide or hydrogen halide (generating nitrilimines or nitrile oxides) and involve the tetrazolate anion as the reactive tetrazole species.1
I.5.3.1. Michael reaction
The Michael reactions of 5-substituted tetrazoles with electron-deficient vinyl systems give the 2-alkylated products in yields of about 50-80 % (Scheme 27).1
Chapter I The 5-Substituted Tetrazoles
16
Scheme 27. Michael reactions of 5-substituted tetrazoles.
I.5.3.2. Acylation
Electrophiles such as acyl halides and imidoyl halides attack the 5-substituted tetrazole ring at the N2-position which can give after thermal decomposition of the Huisgen product
(Scheme 28).
Chapter I Results and discussion
28
I.6. Results and Discussion
I.6.1. Synthesis of tetrazoles
Tetrazole derivatives have attracted much attention as raw materials for medicine, agricultural chemicals, foaming agents, and in the automobile inflator industry. Especially in recent years, remarkable related development has been made in the medicinal field. Yet in order to use tetrazole compounds as starting materials in the fine chemicals field, compounds with high quality polyfunctional structures are required. However, a varsatile method for synthesizing many kinds of tetrazoles through safe and simple manipûlation had not been developed. In this work we have developed a novel synthetic method.
The method involves the reaction of nitrile with an inorganic azide, using an amine salt in an aromatic solvent in a facile workup procedure, to produce tetrazoles with higher purity in greater yield (Scheme29).
Scheme29.
The mechanism of reaction
Chapter I Results and discussion
29
I.6.1.1. Synthesis of tetrazoles from aromatic nitriles
The reaction of 4'-methyl-[1,1'-biphenyl]-2-carbonitrile, 2,2-diphenylacetonitrile and
anthracene-9-carbonitrile with NaN3 at 110°C in the presence of an amine salt for 24h yielding the desired tetrazoles 2b, 2k and 2l in excellent yield (table 1; entries 1, 3 and 4).
The corresponding 2-phenylacetonitrile requires shorter reaction times and provides the tetrazole 2c in good yield using NaN3 at 110°C for only 17 hours (Table 1; entry 2).
Table 1 summarized the physical properties of products prepared as well as gotten
yields.
Table 1: Synthesis of 5-substituted tetrazoles.
Entry Product Time(h) mp(°C) Yield(%)
1 2b 24 149-151 78
2 2c 17 123-124 63
3 2k 24 165-166 72
4 2l 24 215-216 75
Note: Yield after extraction and crystallisation.
The identification of compounds 2b, 2c, 2k and 2l has been established well by
spectroscopic (IR, 1H NMR, 13C NMR) data:
IR Spectroscopy
The IR spectrums of the gotten products showed strong absorption band characteristic of the amino group at
υ
N-H (cm-1)= 2987; 3336, and a second strip of frequency toward 1046; 1053 cm-1 due to stretching of C=C. Function tetrazole is also verified by the presence of band at [2900-2917] cm-1 who corresponds to the C=N link.1
H NMR Spectroscopy
Compound (2b)
The spectrum of this compound showed a singlet (s) absorption band for group CH3 at 2.28 ppm. And aromatic protons appear at [6.98-7.69] ppm which multiplicity appears as follows:
Two doublets (d): the first at 6.98 ppm with coupling constant J= 8.1 Hz, while the second at 7.12 ppm with coupling constant J= 7.9 Hz.
Chapter I Results and discussion
30
Doublet of doublet of doublet (ddd) at 7.55 ppm with coupling constants J= 10.3, 5.8, 1.9 Hz.
The other protons appear at [7.63-7.69] ppm as a multiplet (m) with integration 2H.
Compound (2c)
The spectrum of this compound was characterized by a multiplet (m) at [7.24-7.35] ppm. This multiplet was assigned for 5 aromatic protons. The spectrum also showed a singlet (s) peak at 4.28 ppm for CH2.
Compound (2k)
The spectrum of this compound showed singlet band at 5.85 ppm belong to CH. Also this spectrum showed the multiplet (m) at [7.14-7.37] ppm due to the 10 aromatic protons.
Compound (2l)
Aromatic protons appear at [7.45-8.94] ppm which multiplicity appears as follows: Doublet (d) at 7.45 ppm with coupling constant J= 8.6 Hz with integration 2H.
Two multiplet (m) first at [7.56-7.63] ppm with integration 4H and second at [8.23-8.31] ppm with integration 2H.
Singlet (s) at 8.94 ppm with integration 1H.
The results of 1H NMR of products 2b, 2c, 2k and 2l are summarized in Table 2.
Table 2: 1H NMR for compounds 2b, 2c, 2k and 2l.
Compounds CH CH2 CH3 Harom 2b --- --- 2.28, s, 3H 6.98, d, J= 8.1 Hz, 2H; 7.12, d, J= 7.9 Hz, 2H; 7.55, ddd, J= 10.3, 5.8, 1.9 Hz, 2H; 7.63-7.69, m, 2H 2c --- 4.28, s, 2H --- 7.24-7.35, m, 5H 2k 5.85, s, 1H --- --- 7.14-7.30, m, 10H 2l --- --- --- 7.45, d, J= 8.6 Hz, 2H; 7.56-7.63, m, 4H; 8.23-8.31, m, 2H; 8.94, s, 1H Notes: 1HNMR: (300 MHz, DMSO-d 6).
Chapter I Results and discussion
31
13
C NMR Spectroscopy
Compound (2b)
The spectrum of this compound showed the expected peak for CH3 at 20.7 ppm, the other aromatic carbons appear in the area [123.4-155.1] ppm.
Compound (2c)
The carbon of the group CH2 fate to 29.0 ppm, the aromatic carbons appear at [127.1-155.3] ppm.
Compound (2k)
The spectrum showed the appearance of CH peak at 40.8 ppm. Also this spectrum showed 5 peaks at [128.6-160.0] ppm due to the 13 aromatic carbons.
Compound (2l)
The spectrum showed the aromatic carbons peaks at [120.6-150.1] ppm.
Table 3 summarized all results of 13C NMR for compounds 1b, 1c, 1k and 1l.
Table 3: 13C NMR for compounds 2b, 2c, 2k and 2l.
Compounds CH CH2 CH3 Carom 2b --- --- 20.7 123.4-155.1 2c --- 29.0 --- 127.1-155.3 2k 40.8 --- --- 128.6-160.0 2l --- --- --- 120.6-150.1 Notes: 13CNMR: (75 MHz, DMSO-d 6).
I.6.1.2. Synthesis of 5-substituted heteroaromatic tetrazole
Heteroaromatic nitriles such as picolinonitrile give the corresponding tetrazole 2f in
the presence of an amine salt and NaN3 at 110°C for 24 hours at high temperature with good yield (Table 4; entry 1). The main problem of this substrate is the high hydrophilicity of the
corresponding product which makes difficult the purification with the common extraction procedure.
Table 4 summarized the physical properties of products prepared as well as gotten
Chapter I Results and discussion
32
Table 4: Synthesis of heteroaromatic tetrazoles.
Entry Product Time(h) mp(°C) Yield(%)
1 2f 24 208-210 85
The structure of compound 2f was inferred from spectroscopic (IR, 1H NMR, 13C NMR) data.
1
H NMR Spectroscopy
The spectrum of this product showed two doublet of doublet of doublet (ddd), the first at 7.63 ppm with coupling constants J= 7.8, 4.8, 1.2 Hz, and the second at 8.79 ppm with coupling constants J= 4.8, 1.7, 0.9 Hz. And triply of doublet (td) at 8.08 ppm with coupling constant J= 7.8, 1.7 Hz. Also this spectrum showed a doublet of triplet at 8.22 ppm with coupling constant J= 7.9, 1.0 Hz.
The results of 1H NMR for compound 2f are illustrated in Table 5. Table 5: 1H NMR for compound 2f.
Compound Harom 2f 7.63, ddd, J= 7.6, 4.8, 1.2 Hz, 1H 8.08, td, J= 7.8, 1.7 Hz, 1H 8.22, dt, J= 7.9, 1.0 Hz, 1H 8.79, ddd, J= 4.8, 1.7, 0.9 Hz, 1H 13
C NMR Spectroscopy
The spectrum showed the aromatic carbons peaks at [122.6-154.8] ppm.
I.6.1.3. Synthesis of tetrazoles from alkyl nitriles
The reaction of pivalonitrile, with NaN3 at 110°C in the presence of an amine salt for 17h yielding the desired tetrazole 2d in excellent yield (table 6; entry 1). The tetrazole 2e is
obtained under similar conditions for 30 hours (Table 6; entry 2).
Table 6 summarized the physical properties of products prepared as well as gotten
Chapter I Results and discussion
33
Table 6: Synthesis of 5-substituted tetrazoles from alkyl nitriles.
Entry Products Time(h) mp(°C) Yield(%)
1 2d 17 208-210 90
2 2e 30 72-73 57
The structures of compounds 2d and 2e were inferred from spectroscopic (IR, 1H NMR, 13C NMR) data.
1
H NMR Spectroscopy
Compound (2d)
The spectrum of this compound showed presence of singlet (s) band at 5.85 ppm belongs to 3CH3.
Compound (2e)
The protons of this compound appear at [0.84-2.84] ppm which multiplicity appears as follows:
Tow triplets (t): first at 0.84 ppm with coupling constant J= 6.8 Hz, and second at 2.84 ppm with coupling constant J= 7.6 Hz.
Two multiplet (m): the first at 1.24 ppm with integration 16H, and the second at 1.65-1.68 ppm with integration 2H.
Table 7 summarized all results of 1H NMR for compounds 2d and 2e.
Table 7: 1H NMR for compounds 2d and 2e.
Compounds CH2 CH3 2d --- 1.35, s, 9H. 2e 1.24, m, 16H 1.65-1.68, m, 2H, 2.84, t, J= 7.6 Hz, 2H 0.84, t, J= 6.8 Hz, 3H 13
C NMR Spectroscopy
Compound (2d)In the spectrum of this compound we record the presence of three peaks: the first at 28.9 ppm corresponding to the three CH3, the second at 30.3 ppm corresponding to alkyl C, and the third at 163.4 ppm corresponding to C of tetrazole ring.
Chapter I Results and discussion
34
Compound (2e)
In the spectrum of compound 2e we observe:
The carbon of function CH3 appears at 13.9 ppm. The carbons CH2 resonate in the area [22.2-31.3] ppm. The carbon C of tetrazole ring appears at 155.9 ppm.
The results of 13C NMR for compounds 2d and 2e is illustrated in Table 8.
Table 8: 13C NMR for compounds 2d and 2e.
Compounds C CH2 CH3
2d 30.3, 163.4 --- 28.9
2e 155.9 22.2-31.3 13.9
I.6.1.4. Synthesis of tetrazoles in the presence of carbonyl groups
The treatment of 4,4-dimethyl-3-oxopentanenitrile with NaN3 at 110°C in the presence of an amine salt for 30h yielding the corresponding tetrazole 2j in very good yield (Table 9; entry 1).
Table 9: Synthesis of tetrazole 2j.
Entry Product Time(h) mp(°C) Yield(%)
1 2j 30 152-154 85
1
H NMR Spectroscopy
The spectrum of this compound showed two singlets (s): the first at 1.18 ppm corresponding to protons of three CH3, and the second at 4.41 ppm corresponding to the protons of CH2.
Table 10 summarized all results of 1H NMR for compound 2j.
Table 10: 1H NMR for compound 2j.
Compound CH2 CH3
2j 4.41, s, 2H 1.18, s, 9H
13
C NMR Spectroscopy
Spectral analysis of this compound shows the existence of:
A signal at 25.8 ppm corresponding to the carbons of three CH3, and other at 32.2 ppm corresponding to CH2 group.
Chapter I Results and discussion
35
The carbon of tetrazole ring appears at 128.2 ppm, and the alkyl carbon fate at 44.0 ppm. The assignment of the major 13C NMR signals is summarized in Table 11.
Table 11: 13C NMR for compound 2j.
compound C CH2 CH3 C-C=O C=O
Chapter I Conclusion
36
I.7. Conclusion
The application of sodium azide for the synthesis of 5-substituted tetrazoles is a new efficient process and offers several advantages over many of the previously published procedures, including a reduced environmental impact resulting from the elimination of toxic waste.99,100
The use of sodium azides as an azide source greatly reduces the hazard posed by in
situ generation of hydrazoic acid and avoids formation. The reaction is suitable for use on a
large scale as special care is not required when recycling waste water because the sodium is a non-toxic metal compared to tin organo-metallics. As dialkylaluminum chlorides are available in large quantities and are relatively inexpensive (they are produced for use in Ziegler-Natta catalysis), the reaction is also economically attractive.
In this chapter we have developed a noval synthetic method this method involves the reaction of nitrile with an inorganic azide, using an amine salt in an aromatic solvent in a facile workup procedure, to produce tetrazoles 2b, 2c, 2d, 2e, 2f, 2j, 2k and 2l with higher
purity in greater yield. Our method has several advantages: The reaction produces no byproducts due to side reaction. The reaction takes place rapidly.
Produces the products in excellent yield.
Another characteristic is its simple workup procedures, through which products of excellent purity can be easily isolated. Moreover, the amines and solvents used in the method can be recycled without additional troublesome treatment.
Chapter I Experimental part
37
I.8. Experimental part
General procedure
The mixture of a nitrile (50 mmol), NaN3 (65 mmol) and an amine salt (150 mmol) in an aromatic solvent (100 mL) was heated to 110°C for 17-30 h with stirring. After cooling, the product was extracted with water (100 mL). To the aqueous layer, 36% HCl was added dropwise to salt out the produced tetrazole. After filtration, the solid was dried under reduced pressure, yielding the tetrazole
.
Synthesis of 5-(4'-methyl-[1,1'-biphenyl]-2-yl)-1H-tetrazole (2b)
101Following the general procedure, the reaction of
4'-methyl-[1,1'-biphenyl]-2-carbonitrile (3.94 g, 50 mmol), NaN3 (3.9 g, 65 mmol) and an amine salt (8.22 g, 150 mmol) in toluene at 110°C gave 2b as a brawn solid.
Yield= 78% (3.76 g). Mp= 149-151°C. IR (KBr): 3336, 2974, 2900, 1080, 1046, 879, 755 cm–1. 1HNMR: (300 MHz, DMSO-d6): = 2.28 (s, 3H), 6.98 (d, J= 8.1 Hz, 2H), 7.12 (d, J= 7.9 Hz, 2H), 7.55 (ddd, J= 10.3, 5.8, 1.9 Hz, 2H), 7.63-7.69 (m, 2H). 13CNMR: (75 MHz, DMSO-d6): = 20.7 (CH3), 123.4 (CH), 127.6 (CH) , 128.7 (2xCH), 128.9 (CH), 130.5 (2xCH), 130.6 (CH), 131.1 (C), 136.3 (C),136.8 (C), 141.5 (C), 155.1 (C).
